Global seroprevalence of Toxoplasma gondii infection among patients with mental and neurological disorders: A systematic review and meta‐analysis

Abstract Background and Aim Toxoplasmosis is the most widespread zoonotic disease that affects one‐third of the world's population, and imposes a major public health problem worldwide. This study aimed to assess the prevalence of toxoplasmosis among patients with neuropsychiatric patients. Methods Electronic databases PubMed, Google Scholar, Web of Science, Research Gate, and Scopus were thoroughly searched from February to March 2022 to identify all relevant studies. The quality of studies was evaluated using the Newcastle−Ottawa quality scale for case‐control and cross‐sectional studies. Statistical analysis was done using STATA version 12 software. A random effect model was used to compute the global pooled seroprevalence of Toxoplasma gondii infection. Heterogeneity was quantified by using I 2 value. Subgroup analysis was done, and publication bias was assessed using a funnel plot and Egger's test. Result Of 1250 studies, 49 containing 21,093 participants and conducted in 18 countries were included. The global pooled seroprevalence of T. gondii IgG antibody was 38.27% (95% CI: 32.04−44.9) among neuropsychiatric patients and 25.31% (95% CI: 21.53−29.08) in healthy controls with substantial heterogeneity of 98.3%. The prevalence of T. gondii IgG antibody was higher in males (17.52%) than in females (12.35%) neuropsychiatric patients. The highest pooled prevalence of T. gondii IgG antibody was in Europe (57%) followed by Africa (45.25%) and Asia (43%). Time based analysis showed the highest pooled prevalence of T. gondii IgG antibody in 2012−2016 (41.16%). The global pooled seroprevalence T. gondii IgM antibody among neuropsychiatric patients and healthy controls was 6.78% (95% CI: 4.87−8.69) and 3.13% (95% CI: 2.02−4.24), respectively. Conclusion The pooled prevalence of chronic and acute T. gondii infection among neuropsychiatric patients was 38.27% and 6.78%, respectively. This showed a high burden of toxoplasmosis among neurological and psychiatric patients and urges routine screening of those patients and providing appropriate treatment. It also indicates the need for different stakeholders to develop targeted prevention and control strategies for T. gondii infection.


| INTRODUCTION
Toxoplasmosis is the most widespread zoonotic disease caused by Toxoplasma gondii, which is a single-cell obligate intracellular apicomplexan protozoan parasite that can invade and replicate inside all nucleated cell types of warm-blooded animals. T. gondii infects a one-third of the world's population with a seroprevalence of ranging from 10% to more than 90%. 1,2 It causes potentially serious disease in human and animals resulting in a major public health and economic burden in the world. T. gondii is reported to have a wide spectrum of intermediate hosts, which includes human, sheep, pig, rodents, and birds and harbors the asexual tachyzoite which is the active and lytic form of the parasite that cause life-threatening diseases. The tissue cyst forms of the parasite is a slow-growing stage capable of building cysts mostly in the brain and muscle tissues. [3][4][5] Human beings acquire T. gondii infection through ingestion of the tissue cysts in raw or undercooked meat containing the latent cyst, sporulated oocysts in contaminated water or food, and congenitally from mother to child. 6,7 High prevalence of toxoplasmosis is reported in Africa, Southeast Asia, Middle East, Central/Eastern Europe, and Latin America. Variable prevalence of T. gondii infection was reported in Asia (13.3%−85.3%), Europe (40%−76%), Africa (21.74%−74.8%), North America (7.3%−26.5%). In immunocompetent individuals, T. gondii infection is usually asymptomatic and majority of the parasite is cleared during acute phase infection. Surviving parasites persist as slow-growing bradyzoite tissue cysts, most abundant in tissues with limited immune surveillance, including brain, eye, cardiac, and skeletal muscle. 3 In symptomatic cases, T. gondii is associated with lymphadenopathy, non-flue like symptoms, toxoplasmic retinochoroiditis, ocular toxoplasmosis, and toxoplasmic encephalitis. 7 It also causes sever opportunistic infection in pregnant and other immunocompromised patients due to reactivation of infection in the central nervous system (CNS). 8 The synergetic effect of parasite growth, tissue damage, inflammatory response, host and parasite genotype results in the severity of the diseases. 4 T. gondii is able to produce long-lasting infection and persists in the CNS invading neurons, and functional glial cells leading to various neurological and mental disorders. 9 T. gondii pass the impermeable blood brain barrier (BBB) through several mechanisms such as monocyte and other infected myeloid derived cells extravasate from capillaries to the brain, trans-endothelial migration through attachment of the parasite to CD11b/ICAM1integrins, paracellular entry of the parasite into the CNS through actin-myosin motors, and endothelial lysis. 9,10 Several neurological and mental disorders have been reported in patients with toxoplasmosis such as Alzheimer's disease (AD), schizophrenia, bipolar disorders, generalized anxiety disorder (GAD), obsessive-compulsive disorder, suicidality, Parkinson's disease, epilepsy, depression, dysphoria, and sexual promiscuity. [11][12][13][14][15][16] There are several postulates regarding the chronic neuropathologic mechanisms in toxoplasmosis. These could be downregulation of the glutamate receptor (GLT-1) expression leading to increased level of extracellular glutamate and excitatory glutamatergic signaling and neural damage, and alteration of glutamate decarboxylase 67 (GAD67) which consequently leads to decreased GABAergic synaptic activities. In addition, parasite induced inflammation and overexpression of several cytokines by the infection can contribute to the onset of seizure in T. gondii infected individuals. 4 T.
gondii infection may also lead to impaired catecholamine metabolism resulting psychological, behavioral, and motor changes in infected individuals. 17 Several studies reported that there is a significant association between T. gondii and the various psychiatric and neurological disorders. A recent systematic review reported schizophrenia to be the most frequently linked psychiatric disorder with T. gondii infection. 18 A meta-analysis conducted on the effect of T. gondii on epilepsy reported T. gondii to the main risk factor for epilepsy. 19 Another systematic review and meta-analysis that evaluated the association between T. gondii infection and Parkinson and Alzheimer diseases found a positive association between the parasite and the neuropsychiatric diseases. 20 Although several studies have reported the seroprevalence of T.  (1) Prevalence, seroprevalence, and magnitude, (2) Toxoplasmosis,

| Eligibility criteria
Original articles that reported the seroprevalence of T. gondii infection among patients with any neuropsychiatric disorders were included. Studies reported only in English were included.
However, non-English articles which had abstracts in English that contained the required data for extraction were also included. On the other hand, studies reported the seroprevalence of T. gondii infection among non-neuropsychiatric human study participants and nonhuman subjects (animals, rodents) were excluded. Furthermore, review articles, case reports, and letters to the editor were also excluded.

| Outcome variables
The outcome variable for this study is the global pooled seroprevalence of T. gondii infection (T. gondii IgG and IgM antibodies) among neuropsychiatric patients. using a random effect model. 23 The Cochrane's Q test and I 2 statistics provide an estimate of the percentage of variability in effect estimates that is due to heterogeneity rather than chance alone were used to assess the heterogeneity. The I 2 statistics (percentage of total variability due to heterogeneity) indicates the heterogeneity and its value of 25%, 50%, and 75% corresponds to low, moderate, and high heterogeneity, respectively. 24 Subgroup analysis for the primary outcome was performed in sex, region, country, and year of publication. Moreover, publication bias was assessed by visual observation of the symmetry of the funnel plot, and Egger's test statistics. 25 Sensitivity analysis was done to assess the impact of a single study on the overall pooled effect size. due to duplication, reviews, case reports, letters to the editor, and meta-analysis. Then the abstract and full text of 283 articles were evaluated in detail based on the eligibility criteria and 234 articles were removed due to failure to fulfill the inclusion criteria. Finally, 49 eligible studies were included in this systematic review and metaanalysis. The preferred reporting items for Systematic Review and Meta-analysis (PRISMA checklist 2009) was followed (Figure 1). 26 (Table 1).

| Seroprevalence of chronic T. gondii infection (IgG antibody) among neuropsychiatric patients and healthy controls
Overall, the seroprevalence of T. gondii IgG among patients with neuropsychiatric disorders was variable, ranged from 2.9% reported in Turkey 75 to 85.5% reported in Iran. 59 In this meta-analysis, the global pooled seroprevalence of T. gondii IgG antibody among neuropsychiatric patients was 38.27% (95% CI: 32.04%−44.9%).
There was substantial heterogeneity with I 2 of 98.3% (Figure 2). Comparatively, lower global pooled seroprevalence of T. gondii IgG antibody was found among health controls (25.31%; 95% CI: 21.53−29.08). The seroprevalence of T. gondii IgG among healthy controls ranged from 0.7% reported in Lebanon 2020 44 to 90% reported in Iran. 59 Significant heterogeneity was also observed (I 2 value of 97.9%) (Figure 3).    immunocompromised patients (35.9%), 81 and Ethiopian general population (34.59%). 82 On the other hand, the finding of this study was lower than the prevalence of T. gondii among the Iranian general population (39.3%). 83 The observed variability might be due to differences in the study group, number of studies included in the meta-analysis, and the diagnostic methods employed.  times more likely to develop schizophrenia in their later life than healthy controls. 85 The presence of large amount of bradyzoite in the olfactory bulb and production of large amount of anti T. gondii IgG is associated with the development of anosmia. A compressive review that assessed the association between T. gondii and neurologic disorders found that the increased production of nitric oxide (NO 2 ), enhanced the production of inflammatory cytokines (interferon gamma, tumor necrosis factor alpha, interleukin 1 reactive oxygen and nitrogen species), neurotic biomolecules, and altered the dopamine balance leading to olfactory impairment, migraine, Asperger's syndrome, autism, and schizophrenia. 86,87 According to subgroup analysis, the pooled seroprevalence of T.

| Subgroup analysis
gondii IgG antibody was higher among males 17.52% than in females 12.35%. This finding was in agreement with the finding of a metaanalysis study that assessed toxoplasmosis in Iranian population. 83 With regard to regional classification, a high burden of chronic T.

ACKNOWLEDGMENTS
The authors of this manuscript would like to acknowledge all the authors of the included study and their study participants. In addition, we want to thank all our friends and colleagues who helped us to complete this manuscript.